Inhibition of advanced glycation end products (AGEs): an implicit goal in clinical medicine for the treatment of diabetic nephropathy?
Several factors are incriminated in the genesis of diabetic nephropathy (DN). To elucidate their interplays, we utilized a diabetic rat model with nephropathy (SHR/NDmcr-cp). This model is characterized by hypertension, obesity with the metabolic syndrome, diabetes with insulin resistance, and intrarenal AGE accumulation. Various therapeutic approaches were used to achieve renoprotection. Caloric restriction corrects metabolic abnormalities and protects the kidney without correcting hypertension. Anti-hypertensive agents, angiotensin II receptor blocker (ARB) and calcium channel blocker, lower blood pressure to the same extent, but only ARBs protect the kidney without changes in metabolic abnormalities. Glycemic control is better with insulin than with pioglitazone. The plasma insulin level is increased by insulin but decreased by pioglitazone which worsens the obesity. Nevertheless, pioglitazone provides renoprotection unlike insulin, perhaps as a result of the up-regulation of TGF-beta by hyperinsulinemia. Cobalt up-regulates the expression of a hypoxia-inducible factor (HIF) and its downstream genes (erythropoietin, VEGF, HO-1). It protects the kidney without correcting hypertension and metabolic abnormalities. Altogether, renoprotection is not necessarily associated with blood pressure or glycemic control. By contrast, it is almost always associated with a decreased AGE formation. AGE reduction may reflect a decreased oxidative stress as it is concomitant with a marked reduction of oxidative stress markers.
Miyata
Toshio
T
Center for Translational and Advanced Research, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. t-miyata@mail.tains.tohoku.ac.jp
Dan
Takashi
T
D000818:Animals; D031204:Caloric Restriction; D003035:Cobalt / Q000494:pharmacology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000628:therapy; D004195:Disease Models, Animal; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists; D018384:Oxidative Stress; D051381:Rats; D016896:Treatment Outcome
D017127:Glycation End Products, Advanced; C497444:Hif1a protein, rat; D007004:Hypoglycemic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D003035:Cobalt; C018021:cobaltous chloride